5. How to differentiate between diabetes type 1, 2 and 3

1. An 11-year-old child must leave the classroom several times a day to go to the loo; the child drinks and eats unusual quantities but nevertheless remains thin. These symptoms developed in the course of a few weeks and point to juvenile (type 1) diabetes.
2. A corpulent 50-year-old man is constantly thirsty and drinks a lot. He has difficuly concentrating on his work and he feels tired all day. These problems have existed for many months with increasing intensity. Which leads one to suspect adult-onset (type 2) diabetes.
3. In an Aruban family 8 out of 10 children got insulin dependent diabetes at an early age. This seems to be MODY (type 3 diabetes).

Age
Juvenile (type 1) diabetes generally develops at an age between 2 and 20 years. Adult-onset (type 2) diabetes usually does not manifest itself until middle age (> 40 years) and MODY (type 3 diabetes) comes out between 10 and 25 years (table 1). But in some cases, juvenile diabetes does not cause problems until middle age; adult-onset diabetes can sometimes be diagnosed in youngsters (3) and sometimes MODY can be manifest only after the age of 40 (1).

Table 1. Age at which diabetes generally becomes manifest

Diabetes

Type

Age (years)

juvenile

1

2 - 20

adult-onset

2

> 40

MODY

3

10 - 25

Case 1 (from the handbook 'Interne geneeskunde')
Ms J., 57 years old, suffers from thirst and fatigue to an increasing extent. She is no longer able to carry out her work activities as an accountant. The numbers start to dance before her eyes after only a few hours; she cannot concentrate and as the afternoon progresses, she feels dead tired. These symptoms developed gradually over the course of a few weeks. She has difficulty sleeping because of her thirst and because she has to urinate often. During the past week, she has had to drink at least a litre every night. Upon inquiry by the general practitioner, it was found that she has always been in good health. According to her, there is no history of diabetes in her family.
She does not appear to be ill, but she does seem severely tired. Her body weight is 63 kg at a height of 1.69 m. Her blood pressure is 125/70 mmHg. What strikes the eye are the vitiligo segments on the back of her hand and lower arm. The peripheral vessels pulsate adequately and there are no heart murmurs. Lab tests confirm the probability of the diagnosis: the fasting plasma glucose level of the blood is 22 mmol/l. In view of her age, she is diagnosed with type 2 diabetes and treated with 1 mg of glimepiride per day. After a week, a fasting plasma glucose level of 9 mmol/l is measured. And the symptoms worsen again after a few weeks, despite increasing the dosage of glimepiride. When the patient became extremely nauseous and could no longer keep any food or fluids down, she was found to be in keto-acidosis upon being taken to the emergency ward.

The diagnosis of type 2 diabetes was made too readily based on age alone and was most likely incorrect. Type 1 diabetes frequently comes about at a juvenile age indeed, but it can be manifest only at old age. If the classic characteristics of type 2 diabetes (family medical history, overweight, high blood pressure and an altered lipids profile in the blood) are lacking, then the diagnosis of type 1 diabetes should be considered. This certainly applies if there are symptoms that point to auto-immunity, as was the case with this patient (vitiligo). In case of doubt, it is wise to treat with insulin in expectation of diagnostics (antibodies that target GAD antigen) (3).

Anti-GAD
In type 1 diabetics, the β-cells have been shut down due to an auto-immune reaction. That process of inflammation causes antibodies that target GAD (Glutamic Acid Decarboxylase), an enzyme that helps in the production of insulin (4). So the presence of antibodies that target GAD demonstrates the auto-immune reaction and is therefore evidence of type 1 diabetes. In the case of adult-onset diabetes or MODY, an auto-immune reaction against the β-cells does not occur and so the anti-GAD test is then negative. But anno 2017, the anti-GAD test is carried out only in some certified laboratories (in the Netherlands) and not in the regular labs for general practitioners.

C-peptide
The blood of type 1 diabetics no longer contains naturally produced insulin because the β-cells in these patients have been shut down (4). In the case of adult-onset diabetes and MODY on the other hand, some natural insulin is still present in the blood. That can be demonstrated, even when external insulin has been administered to a diabetic. In the natural production of insulin by the β-cells, pro-insulin is split up into equal amounts of insulin and C-peptide (Connecting-peptide) (4). No C-peptide is formed in the production of synthetic insulin. Therefore the presence of this substance in the blood points to the production of natural insulin (2). So a type 1 diabetic who is injected with synthetic insulin, has insulin in his blood indeed, but no C-peptide. Alternately, the presence of C-peptide can be demonstrated in those suffering from adult-onset diabetes or MODY. But C-peptide determinations need special medical grounds in The Netherlands.

DNA
Due to ignorance, MODY in children and youngsters is sometimes mistaken for type 1 diabetes (1). And if discovered at a mature age, it can be mistaken for adult-onset diabetes. As a consequence, people with MODY are not always properly treated. The anti-GAD test is negative, because there is no auto-immune reaction in the pancreas, and the C-peptide test is positive in MODY patients, because there is some residual insulin production, just like in adult-onset diabetics. So to distinguish between type 2 and type 3 diabetes these blood tests are not helpful. But the gene-variants in the DNA are different indeed. So DNA-research can be conclusive between adult-onset diabetes and MODY. The same DNA-research is needed to distinguish between the different types of MODY (1-10). However, in the Netherlands, the gene-variant concerned in humans with MODY is confirmed by DNA-analysis in only 5% of all 20.000 MODY patients (1). Yet that is important for the choice of treatment, which is different for each gene-variant. But, until now, it is only carried out in specialized laboratories and DNA-analysis does not make up part of the routine in making diabetes diagnoses. Because neither the anti-GAD or C-peptide tests are part of routine diabetes diagnosing, the distinction between diabetes type 1, 2 and 3 mainly depends on the age of the patients.

Too high values for FPG and glycated hemoglobin illustrate manifest diabetes. The absence of antibodies against GAD indicates that there is no auto-immune reaction in the pancreas against β-cells and, as a consequence, this patient is not suffering from diabetes type 1. The concentration of C-peptide in the blood is too low. So the insulin production is less than normal. That indicates for type 2 or type 3 diabetes. Next DNA research for MODY(1-10) rules out type 3 diabetes. Thus the diagnosis in this patient is: type 2 diabetes (adult-onset diabetes) in spite of her juvenile age.

Conclusions
1. The age alone does not offer enough to go on in differentiating between diabetes type 1, 2 and 3.
2. In juvenile (type 1) diabetics the anti-GAD test is positive, the C-peptide test is negative.
3. In adult-onset (type 2) diabetics the ant-GAD test is negative, the C-peptide test is positive but too low.
4. In humans with MODY (type 3), the anti-GAD-test is negative, the C-peptide test is positive but too low.
5. DNA-research distinguishes between MODY and adult-age diabetes and between different types of MODY(1-10).